S275: ALTERATION OF IRON HOMEOSTASIS THROUGH GENETIC AND PHARMACOLOGIC MODULATION OF FERROPORTIN MODIFIES MDS PATHOPHYSIOLOGY IN A PRECLINICAL MOUSE MODEL
Authors: S. Z. Vance, A. Antypiuk, R. Sharma, F. Dürrenberger, V. Manolova, F. Vinchi
Journal: HemaSphere (2022)

Background: Patients with myelodysplastic syndromes (MDS) are prone to develop iron overload as a consequence of ineffective erythropoiesis and chronic transfusion therapy. Although iron overload is a common feature in MDS, it remains unclear whether and how iron excess is detrimental for MDS pathophysiology. Aims: This study aimed at characterizing altered iron homeostasis in a preclinical MDS mouse model, understanding the molecular mechanisms underlying iron toxicity and unraveling the potential therapeutic value of pharmacologic iron restriction in this disease condition. Methods: To this end, we took advantage of complementary approaches and analyzed the effect of iron overload obtained through genetic activation of the iron exporter ferroportin (FPNC326S), and iron restriction achieved through the administration of the FPN inhibitor Vamifeport for 3 months in NUP98-HOXD13 MDS mice. Mice were analyzed at 6 months of age. Results: MDS mice develop anemia and low white blood cell counts in the peripheral blood associated with a significant iron overload phenotype, hallmarked by low hepcidin levels, elevated serum iron and transferrin saturation, non-transferrin-bound iron (NTBI) formation and tissue iron deposition. FPNC326S MDS mice show an aggravated iron phenotype, with further elevated NTBI and tissue iron accumulation and still inappropriately low hepcidin levels. Vamifeport administration in MDS mice reduced serum iron and NTBI levels and prevented tissue iron loading. While iron excess in FPNC326S MDS mice did not improve erythropoiesis and hematologic parameters in the peripheral blood, iron restriction by Vamifeport significantly ameliorated red blood cell maturation and hemoglobin levels in MDS mice. The improved ineffective erythropoiesis was associated with reduced oxidative stress and apoptosis in erythroid progenitors. Unexpectedly, we observed a major role of the iron status in myeloid expansion in MDS. The number of immature myeloid blasts and myeloid progenitors as well as inflammation markers in the bone marrow of MDS mice were aggravated by iron overload in FPNC326S MDS mice and attenuated by iron restriction in Vamifeport-treated MDS mice compared to control MDS animals. Myeloid bias, monitored as percentage bone marrow myeloid cells, was exacerbated by iron overload and alleviated by iron restriction. Overall, this translated into a faster and delayed transition to AML, respectively. Finally, iron showed a profound impact on the stem cell pool in MDS. Iron overload aggravated and iron restriction alleviated the formation of reactive oxygen species, accumulation of DNA damage and levels of the apoptosis marker annexin V in hematopoietic stem and progenitor cells (HSPCs). By reducing the intracellular labile iron pool, Vamifeport improved HSPC quality and survival, partially rescuing the stem cell pool size in MDS mice. The improved stem cell pool, reduced myeloid bias and attenuated anemia resulted in a significant survival increment in iron-restricted compared to control MDS mice. Summary/Conclusion: Our results show for the first time in a preclinical mouse model of MDS that iron excess driven by ineffective erythropoiesis has pathological implication in transfusion-independent MDS. These effects are likely aggravated by transfusions causing additional iron overload. Finally, iron restriction achieved through pharmacologic FPN inhibition significantly improves MDS pathophysiology, uncovering the therapeutic potential of early prevention of NTBI formation in MDS.